Title: Physiology of Inflammatory Arthritis in High Resolution Abstract Development of new imaging technologies to identify and validate biomarkers of inflammatory arthritic disease is of broad interest and aligned with common goals of physicians, medical researchers, and scientific entities. Presenting highly sensitive optical information in subsurface tissue with spatial resolution comparable to ultrasound (US) imaging, the emerging photoacoustic (PA) imaging offers significant advantages to early diagnosis and prognosis, as well as assessing the treatment of arthritis, by providing additional new functional information about the disease activity that can be effectively combined with more established and widely accepted musculoskeletal US imaging. Our current research on arthritis patients has successfully demonstrated that a combined US-PA system is capable of identifying and characterizing inflammation in human peripheral joints, based on the detection of hemodynamic and metabolic changes, including both hyperemia and hypoxia. These are important and early physiological biomarkers of synovitis reflecting the increased metabolic demand and the relatively inadequate oxygen delivery of the inflammatory synovial tissue. Encouraged by the initial success of our study on arthritis patients, we propose to further advance the translation of US-PA dual imaging technology to clinical management of inflammatory arthritis. Our ultimate goal is to develop a cost-efficient and point-of-care joint imaging device that can enable early treatment modification and personalized medicine, changing the current procedures in rheumatology clinic. In this research, to understand the clinical value of the proposed imaging technology, we will identify a group of robust, reliably reproducible, and precise biomarkers that can reflect the early pathological changes of inflammatory arthritis and its response to treatment. The central hypothesis is that a group of 3D US and PA biomarkers that can be evaluated by the proposed imaging technology can lead to better assessment of arthritis disease state and treatment response than those evaluated by conventional 2D US imaging. To examine this hypothesis, following specific aims will be accomplished: Aim 1: Develop a method to assess inflammatory arthritis disease activity by quantifying 3D US and PA biomarkers that reflect the underlying pathological condition of specific joints Aim 2: Evaluate the performance of these biomarkers in assessing the pathological condition in local joints affected by arthritis through the study on a well-developed animal model Aim 3. Evaluate the clinical value of the identified imaging biomarkers that can be assessed by the US-PA dual-modality technology via a pilot study on patients affected by inflammatory arthritis